Approximately 30-40% of atherosclerotic coronary arteries treated by angioplasty or by bypass surgery occlude as a result of restenosis. Vascular smooth muscle cell (VSMC) proliferation and migration are critical events in the development of restenosis and in the progression of atherosclerosis.
Percutaneous transluminal angioplasty (PTA), defined as any percutaneous transluminal method of decreasing stenosis within a blood vessel, whether caused by the existence of an atheromatous plaque, thrombosis, embolus, and/or mineral deposit, by any of a number of means such as balloon dilation, thermal ablation, laser atherectomy, mechanical shaving, extraction or ultrasonic pulverization, hereinafter referred to as angioplasty, is widely used in the treatment of occlusive vascular disease. However, it has been found that restenosis frequently occurs, and in the case of coronary angioplasty, restenosis occurs in about a third of cases within 6 months of the procedure.
Angiotensin converting enzyme (ACE) inhibitors or the physiologically tolerable salts thereof have been used in the treatment of atherosclerosis, thrombosis and/or peripheral vascular disease in mammals. It has been disclosed that, because ACE is predominantly localized in the luminal plasma membrane of the endothelial cell, ACE inhibitors can interfere in platelet-endothelium interaction. In addition, ACE inhibition potentiates the action of bradykinin (a strong stimulator of prostacyclin release from endothelial cells) by inhibiting its degradation. ACE inhibitors, consequently, have an inhibitory effect on platelet aggregation (See U.S. Pat. Nos. 5,140,012 and 5,166,143). In large scale clinical trials, ACE inhibitors have failed to demonstrate a beneficial effect in preventing restenosis following angioplasty.
Other methods for preventing restenosis after angioplasty include combining photoactivatable psoralen and ultraviolet radiation, as set forth in U.S. Pat. No. 5,116,864, and radiation from a source of radioactivity, as set forth in U.S. Pat. No. 5,213,561.
Recently, a gene has been discovered, that is present in certain families resident in Limone, Italy, which codes for a protein that may have the function of preventing the build-up of fatty deposits that clog the arteries and may be especially effective in preventing the reclogging of arteries that occurs after a blocked vessel has been cleared with balloon angioplasty surgery.
A commonly assigned, co-pending application, U.S. Ser. No. 08/794,289, describes methods of using RAR-selective retinoids and retinoid pan-agonists in treating restenosis.
A commonly assigned, co-pending application, U.S. Ser. No. 08/466,000, of Chandraratna, et al. describes 2,4-pentanedioic acid derivatives which have RXR-retinoid activity. Additionally, published PCT application 97/12853 discloses a variety of compounds which are dimer-selective RXR modulators.
Further, commonly assigned U.S. Pat. No. 5,455,265 and a divisional application pending therefrom describes and claims methods of treatment with certain compounds having selective agonist-like activity on RXR retinoid receptors.
Published PCT application 96/33724 discloses ligands that bind to and modulate the processes mediated by peroxisome proliferator activated receptor--gamma (PPAR.gamma.).
The above-mentioned patents and pending patent applications are incorporated herein by reference in their entirety. The portion of commonly assigned U.S. Pat. No. 5,455,265 to Chandraratna which details assays which are known and used in the art to measure RXR agonist activity and are described from column 5, line 37 through column 11, line 58 is specifically and expressly incorporated herein by reference.
To date, none of the present methods for preventing restenosis are suitable in every aspect. Therefore, the search for methods for preventing the onset of restenosis after angioplasty continues.